Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people over age 60 and an estimated 8 million older-age Americans are at high risk to develop advanced AMD. Among two types of AMD, neovascular (wet) and non-neovascular (dry), neovascular AMD causes 90% of the vision loss. The key pathogenesis of the neovascular AMD is neovascularization and its associated increased vascular permeability in the macula. It eventually leads to photoreceptor degeneration causing central vision loss. Although with the most advanced treatment including the newly FDA approved anti-VEGF treatments (Macugen(R), Lucentis(R)/Avastin(R)), there are only 25-33% patients with visual acuity improvement. Even for the well-responded individual, re-occurring neovascularization after a few months often require repeated treatments. Therefore, AMD clinical management remains a great challenge with the need for more effective therapies. The multifactor nature involved in the pathogenic process of AMD requires pursuing novel agents to target other factors promoting angiogenesis, such as inflammation, as an alternative therapy or in combination therapy with anti-VEGF agents. The objective of this proposal is to determine the role of APE1/Ref-1 in retinal angiogenesis and evaluate the potential of APE1/Ref1 as a new therapeutic target for treatment of neovascularization using in vitro retinal endothelial cells and in vivo animal models of AMD with subretinal and choroidal neovascularization. The hypothesis of the proposed research is that blocking APE1/Ref-1 redox function will lead to inhibition of retinal neovascularization as a single agent efficacy, as well as enhancement of anti-VEGF treatments in AMD. Specific Aim 1: Characterization of the novel agent, (2E)-3-[5-(2, 3-dimethoxy-6-methyl-1,4-benzoquinoyl)]-2- nonyl-2-propenoic acid (APX3330) and new novel analogues of APX3330 on APE1/Ref-1's function in retinal vascular endothelial cells (RVEC). Specific Aim 2: Determination of APX3330 and new novel analogues on APE1/Ref-1's function in animal models of AMD. We will study the anti-angiogenic effects of APX3330 on subretinal neovascularization (SNV) in vldlr-/- mice and on choroidal neovascularization (CNV) in laser-induced CNV animal model. We anticipate two outcomes: enhancement of currently used anti-VEGF agents such as Macugen and Lucentis(R) and the development of a new single agent that would augment or supplement current and future use of anti-VEGF treatments. This enhanced anti-angiogenic effect may allow for longer treatment intervals or enhance the efficacy of anti-VEGF agents. Other indications/utility: We also see potential utility of APE1/Ref-1 redox inhibition in other indications such as diabetic retinopathy and other scenarios where anti-angiogenic agents could or are being used such as cancer, glaucoma and other diseases. PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of severe vision loss in people over age 60 and an estimated 8 million older-age Americans are at high risk to develop advanced AMD. AMD clinical management remains a great challenge with the need for more effective therapies. The proposed work will look at the effects of APE1/Ref-1 redox inhibitors in cells and in animals toward the goal of enhancing of current therapies and the development of a new therapy for treating AMD.